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Ubiquitin-specific protease 22 ameliorates chronic alcohol-associated liver disease by regulating BRD4
- Source :
- Pharmacological research. 168
- Publication Year :
- 2021
-
Abstract
- Alcohol-associated liver disease (ALD) is a liver system disease caused by alcohol abuse, and it involves complex processes ranging from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma. Steatosis and inflammation are the main phenomena involved in ALD. Ubiquitin-specific protease 22 (USP22) plays an important role in liver steatosis; however, its functional contribution to ALD remains unclear. USP22-silenced mice were fed a Lieber-DeCarli liquid diet. AML-12 and HEK293T cells were used to detect the interaction between USP22 and BRD4. Here, we report that hepatic USP22 expression was dramatically upregulated in mice with ALD. Inflammation and steatosis were significantly ameliorated following USP22 silencing in vivo, as indicated by decreased IL-6 and IL-1β levels. We further showed that the overexpression of USP22 increased inflammation, while knocking down BRD4 suppressed the inflammatory response in AML-12 cells. Notably, USP22 functioned as a BRD4 deubiquitinase to facilitate BRD4 inflammatory functions. More importantly, the expression levels of USP22 and BRD4 in patients with ALD were significantly increased. In conclusion, USP22 acts a key pathogenic factor in ALD by deubiquitinating BRD4, which facilitates the inflammatory response and aggravates ALD.
- Subjects :
- 0301 basic medicine
Male
Cirrhosis
Inflammation
Cell Cycle Proteins
Deubiquitinating enzyme
03 medical and health sciences
Liver disease
Mice
0302 clinical medicine
Downregulation and upregulation
Fibrosis
medicine
Gene silencing
Animals
Humans
Liver Diseases, Alcoholic
Cells, Cultured
Pharmacology
biology
business.industry
Ubiquitination
medicine.disease
Mice, Inbred C57BL
030104 developmental biology
030220 oncology & carcinogenesis
biology.protein
Cancer research
Female
Steatosis
medicine.symptom
business
Ubiquitin Thiolesterase
Transcription Factors
Subjects
Details
- ISSN :
- 10961186
- Volume :
- 168
- Database :
- OpenAIRE
- Journal :
- Pharmacological research
- Accession number :
- edsair.doi.dedup.....7427dd8cf6f5d0c7b0f47bde3c9e6ee8